Durvalumab plus tremelimumab effective for patients with progressive, refractory advanced thyroid carcinoma

The DUTHY trial investigated whether dual targeting of PD-L1 and CTLA-4 could improve the efficacy of immunotherapy in advanced thyroid cancers (TC). Durvalumab plus tremelimumab was tolerable and showed promising activity in heavily pretreated advanced differentiated TC and medullary TC. In the anaplastic TC cohort, durvalumab and tremelimumab demonstrated significant and clinically meaningful efficacy with prolonged overall survival, granting further research.

Thyroid cancer is the most common endocrine malignancy, although it is a rare tumour in advanced stages. To date, there is no effective therapy for patients with advanced differentiated thyroid carcinoma (DTC) and medullary thyroid carcinoma (MTC) after progression to approved multikinase inhibitors (MKIs). Targeting PD-L1/PD-1 in monotherapy has proven limited efficacy in advanced DTC and MTC, and promising activity in anaplastic cancer (ATC) patients. Dual targeting of PD-L1 and CTLA-4 could improve the efficacy of immunotherapy. Early experience with dual immune-checkpoint inhibitors showed considerable activity in ATC and responses were seen in DTC.

Study design

DUTHY was a prospective, open-label trial that recruited patients with thyroid cancer in three cohorts (C1-3): differentiated thyroid cancer (C1, including the subtypes of papillary, follicular, poorly differentiated and Hürtle cell carcinoma after progression to lenvatinib or progression on at least two prior TKIs which may or not include lenvatinib), medullary thyroid cancer (C2, after progression to vandetanib or progression to at least two prior TKIs that may or not include vandetanib), and anaplastic thyroid cancer (C3, regardless of prior therapy). No prior immunotherapy was allowed. Patients received durvalumab 1500 mg and tremelimumab 75 mg every 4 weeks, up to 4 cycles, followed by durvalumab monotherapy until confirmed disease progression, or unacceptable toxicity. Primary objective was 6-month progression-free survival (PFS) rate for C1 and C2 and 6-month overall survival (OS) rate for C3. Secondary objectives included safety and efficacy in terms of objective response rate (ORR), median PFS and OS. The expected accrual was 37/37/12 patients respectively for C1-3.

Results

From April 2019, 68 patients were enrolled in the DUTHY trial; 37 in C1, 19 in C2 and 12 in C3. C1 and C3 completed accrual, C2 completed the first stage and the second stage is open for recruitment. Median age of the participants was 66 years and 58.8% were female. Patients received a median of 2, 2 and 0 previous treatment lines for C1-3, respectively. Surgery of the primary tumour was performed in 94.6%, 84.2% and 16.7% of patients in C1, C2 and C3, respectively. The median follow-up was 12.2 months, 16.8 months and 11.5 months, with a 6-month PFS rate of 32.4%, 37.5% and 33.3% for C1, C2 and C3, respectively. The corresponding median PFS was 5.3 months, 5.3 months and 4 months. The 6-month OS rate was 70.3%, 93.8% and 65.6%, with a median OS of 12.5 months, not reached and 13.8 months, for C1, C2 and C3, respectively.  The ORR according to RECIST 1.1 was 8.1%, 15.8%, 33.3% for C1-3 respectively. In C3, the ORR was 50% in PD-L1 positive patients while it was 0% in PD-L1 negative patients. Patients received a median of five and four cycles for durvalumab and tremelimumab, respectively. In total, 47 (71.2%) patients experienced toxicities, with 10 (15.2%) patients experiencing grade ≥3 toxicities. The most common treatment-related adverse events of any grade were pruritus (24.2%), fatigue (18.2%), other skin and subcutaneous disorders (16.7%) and diarrhea (15.2%). The toxicity was similar to previous trials with durvalumab and tremelimumab.

Conclusion

The combination of durvalumab and tremelimumab was found to be tolerable in thyroid cancer. Dual checkpoint blockade showed modest activity in heavily pretreated advanced DTC and MTC. The MTC cohort is still open for recruitment. In the ATC cohort, dual checkpoint blockade obtained clinically meaningful efficacy with prolonged OS and ORR. Translational studies are ongoing.

Reference

Capdevila Castillon J, et al. Durvalumab (D) plus tremelimumab (T) for the treatment of patients with progressive, refractory advanced thyroid carcinoma: The DUTHY (GETNE-T1812) trial. Presented at ESMO 2022; Abstract 1645O.